A 22-year-old man undergoes screening colonoscopy and is found to have more than 100 adenomatous polyps. Genetic testing shows a truncating mutation of the APC gene. Accumulation of which protein explains adenoma formation in this condition?

• A SMAD4, leading to failure of TGF-beta growth inhibition
• B PTEN, resulting in constitutive PI3K-AKT signalling
• C K-Ras, locked in its GTP-bound active conformation
• D Beta-catenin, which enters the nucleus and activates MYC and cyclin D1 transcription ✓

Explanation

Normal APC forms the destruction complex that ubiquitinates beta-catenin, keeping cytoplasmic levels low. Truncated APC cannot degrade beta-catenin, so it accumulates, translocates to the nucleus, partners with TCF, and drives transcription of MYC and cyclin B1. Option C describes the separate KRAS mutation step of the adenoma-carcinoma sequence, and option A describes the later SMAD4 alteration, both of which typically follow APC loss rather than initiate polyposis.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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